谷口 良輔

<h4>Background</h4>Arteriovenous fistulae (AVFs) are the preferred vascular access for hemodialysis in patients with end-stage kidney disease. Chronic kidney disease (CKD) is associated with endothelial injury, impaired AVF maturation, and reduced patency, as well as utilization. Because CKD is characterized by multiple pathophysiological processes that induce endothelial-to-mesenchymal transition (EndMT), we hypothesized that CKD promotes EndMT during venous remodeling and that disruption of endothelial TGF (transforming growth factor)-β signaling inhibits EndMT to prevent AVF failure even in the end-stage kidney disease environment.<h4>Methods</h4>The mouse 5/6 nephrectomy and aortocaval fistula models were used. CKD was created via 5/6 nephrectomy, with controls of no (0/6) or partial (3/6) nephrectomy in C57BL/6J mice. AVFs were created in mice with knockdown of TGF-βR1/R2 (TGF-β receptors type 1/2) in either smooth muscle cells or endothelial cells. AVF diameters and patency were measured and confirmed by serial ultrasound examination. AVF, both murine and human, were examined using Western blot, histology, and immunofluorescence. Human and mouse endothelial cells were used for in vitro experiments.<h4>Results</h4>CKD accelerates TGF-β activation and promotes EndMT that is associated with increased AVF wall thickness and reduced patency in mice. Inhibition of TGF-β signaling in both endothelial cells and smooth muscle cells decreased smooth muscle cell proliferation in the AVF wall, attenuated EndMT, and was associated with reduced wall thickness, increased outward remodeling, and improved AVF patency. Human AVF also showed increased TGF-β signaling and EndMT.<h4>Conclusions</h4>CKD promotes EndMT and reduces AVF patency. Inhibition of TGF-β signaling, especially disruption of endothelial cell-specific TGF-β signaling, attenuates EndMT and improves AVF patency in mouse AVF. Inhibition of EndMT may be a therapeutic approach of translational significance to improve AVF patency in human patients with CKD.

<h4>Background/aim</h4>Incisional hernia is among the most prevalent complications associated with open abdominal aortic aneurysm repair. However, risk factors for incisional hernias in patients with abdominal aortic aneurysm are multifactorial. Therefore, this study evaluated the risk factors of incisional hernia after open abdominal aortic aneurysm repair, including surgical factors.<h4>Patients and methods</h4>We retrospectively extracted data from patients with incisional hernias after abdominal aortic aneurysm repair between 2012 and 2019 and investigated their perioperative characteristics and wound closure techniques.<h4>Results</h4>The mean follow-up periods were 41.5±30.3 months, and 30 of 131 (22.9%) patients suffered an incisional hernia. Regarding the underlying disease, only diabetes mellitus was significantly more common in the incisional hernia group (11 of 30 patients, 36.6%), and no significant differences were found in the patients' perioperative data. Interrupted sutures were used in all 30 patients in the hernia group. Moreover, in 8 of the 101 remaining cases, barbed sutures were used, and no incisional hernia occurred in any of these cases.<h4>Conclusion</h4>In addition to diabetes mellitus, abdominal aortic aneurysm is a significant risk factor for incisional hernia after abdominal aortic aneurysm repair. Therefore, employing the barbed suture technique may effectively prevent incisional hernias after abdominal aortic aneurysm repair.

<h4>Purpose</h4>Surgical procedures are often evaluated subjectively, and an objective evaluation has been considered difficult to make and rarely reported, especially in open surgery, where the range of motion is wide. This study evaluated the effectiveness of surgical suturing training as an educational tool using the Leap Motion Controller (LMC), which can capture hand movements and reproduce them as data comprising parametric elements.<h4>Methods</h4>We developed an off-the-job training system (Off-JT) in our department, mainly using prosthetic grafts and various anastomotic methodologies with graded difficulty levels. We recruited 50 medical students (novice group) and 6 vascular surgeons (expert group) for the study. We evaluated four parameters for intraoperative skills: suturing time, slope of the roll, smoothness, and rate of excess motion.<h4>Results</h4>All 4 parameters distinguished the skill of the novice group at 1 and 10 h off-JT. After 10 h of off-JT, all 4 parameters of the novices were comparable to those of the expert group.<h4>Conclusion</h4>Our education system using the LMC is relatively inexpensive and easy to set up, with a free application for analyses, serving as an effective and ubiquitous educational tool for young surgeons.

T cells and macrophages play an important role in the formation of allograft vasculopathy, which is the predominant form of chronic rejection in cardiac transplants. Arteries express Ephrin-B2 as a marker of arterial identity, whereas circulating monocytes express the cognate receptor EphB4, which facilitates monocyte adhesion to the endothelial surface. Adherent monocytes transmigrate and differentiate into macrophages that activate T cells and are a main source of tissue damage during rejection. We hypothesized that inhibition of Ephrin-B2-EphB4 binding would decrease immune cell accumulation within a transplanted graft and prevent allograft vasculopathy. We used EphB4 monomer to inhibit Ephrin-B2-EphB4 binding in a rat infrarenal aortic transplant model. Rats treated with EphB4 monomer had fewer macrophages and T cells in the aortic allografts at 28 days, as well as significantly less neointima formation. These data show that the Ephin-B2-EphB4 axis may be an important target for prevention or treatment of allograft vasculopathy.

We have described a case of multiple surgeries for a ruptured popliteal artery in an 11-year-old female patient with vascular Ehlers-Danlos syndrome. She underwent emergency hematoma evacuation and ruptured popliteal artery interposition with the great saphenous vein graft, which was notably fragile during surgery and had ruptured on the seventh postoperative day. We performed another emergency hematoma evacuation and popliteal artery interposition with an expanded polytetrafluoroethylene vascular graft. Despite the early occlusion of the expanded polytetrafluoroethylene graft, she recovered with mild intermittent claudication in the left lower extremity and was discharged on postoperative day 20 after the first surgery.

<h4>Objective</h4>Type III endoleaks after endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms (AAAs) with the Endologix unibody endograft remain a major concern, despite fabric, system, and instructional updates. The purpose of this study was to examine real-world outcomes of repairing AAAs using the current version of the AFX2 main body in combination with an aortic cuff, specifically focusing on type III endoleaks and morphological changes of the endograft.<h4>Methods</h4>We recruited facilities in Japan that used AFX2 combined with an aortic cuff for at least five cases between April 2017 and March 2018. A total of 175 cases in 24 facilities were analyzed. Patients' background information, including anatomic factors, operative findings, device component variations, and midterm outcomes at 3 years after the EVAR were collected. The data on computed tomography scans from cases registered as types I and III endoleaks and migration from each institute were sent to our department for verification.<h4>Results</h4>The mean patient age was 74.6 ± 8.1 years, and 48 cases (27%) were saccular aneurysms. The mean fusiform and saccular AAA diameters were 50.5 ± 5.8 mm and 43.5 ± 8.9 mm, respectively. No in-hospital deaths occurred. Data at 3 years, including computed tomography images, of 128 cases were analyzed. Overall survival, freedom from aneurysm-related mortality, and freedom from reintervention rates at 3 years were 85.8%, 99.3%, and 87.3%, respectively. There were three, one, and three cases of types I, IIIa, and IIIb endoleaks without sac dilatations, respectively. Among five migration cases, one case of aortic cuff migration presented as a type Ia endoleak, and four cases demonstrated sideways displacement, one of which presented as a type IIIa endoleak. The sac regression and enlargement rates at 3 years were 41.4% and 20.5% in the fusiform group and 44.2% and 16.7% in the saccular group, respectively. The proximal neck diameter slightly increased from 20.8 ± 2.7 mm before the EVAR to 22.2 ± 4.6 mm after the repair.<h4>Conclusions</h4>Midterm outcomes of the AFX2 used in combination with an aortic cuff were acceptable, considering the rates of types I and III endoleaks. However, there were cases of sideways displacement that could cause future type IIIa endoleaks. When the AFX2 is used in combination with an aortic cuff, close surveillance for endograft deformations and subsequent adverse events, including type III endoleaks, is needed.

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Endovascular treatment of atherosclerotic arterial disease exhibits sex differences in clinical outcomes including restenosis. However, sex-specific differences in arterial identity during arterial remodeling have not been described. We hypothesized that sex differences in expression of the arterial determinant erythropoietin-producing hepatocellular receptor interacting protein (Ephrin)-B2 occur during neointimal proliferation and arterial remodeling.</jats:p> </jats:sec><jats:sec> <jats:title>Methods and results</jats:title> <jats:p>Carotid balloon injury was performed in female and male Sprague–Dawley rats without or 14 days after gonadectomy; the left common carotid artery was injured and the right carotid artery in the same animal was used as an uninjured control. Arterial hemodynamics were evaluated in vivo using ultrasonography pre-procedure and post-procedure at 7 and 14 days and wall composition examined using histology, immunofluorescence and Western blot at 14 days after balloon injury. There were no significant baseline sex differences. 14 days after balloon injury, there was decreased neointimal thickness in female rats with decreased smooth muscle cell proliferation and decreased type I and III collagen deposition, as well as decreased TNFα- or iNOS-positive CD68+ cells and increased CD206− or TGM2-positive CD68+ cells. Female rats also showed less immunoreactivity of VEGF-A, NRP1, phosphorylated EphrinB2, and increased Notch1, as well as decreased phosphorylated Akt1, p38 and ERK1/2. These differences were not present in rats pretreated with gonadectomy.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Decreased neointimal thickness in female rats after carotid balloon injury is associated with altered arterial identity that is dependent on intact sex hormones. Alteration of arterial identity may be a mechanism of sex differences in neointimal proliferation after arterial injury.</jats:p> </jats:sec>

<h4>Background</h4>Arteriovenous fistulae (AVF) are the gold standard for vascular access for hemodialysis. Although the vein must thicken and dilate for successful hemodialysis, excessive wall thickness leads to stenosis causing AVF failure. Since TGF-β (transforming growth factor-beta) regulates ECM (extracellular matrix) deposition and smooth muscle cell (SMC) proliferation-critical components of wall thickness-we hypothesized that disruption of TGF-β signaling prevents excessive wall thickening during venous remodeling.<h4>Methods</h4>A mouse aortocaval fistula model was used. SB431542-an inhibitor of TGF-β receptor I-was encapsulated in nanoparticles and applied to the AVF adventitia in C57BL/6J mice. Alternatively, AVFs were created in mice with conditional disruption of TGF-β receptors in either SMCs or endothelial cells. Doppler ultrasound was performed serially to confirm patency and to measure vessel diameters. AVFs were harvested at predetermined time points for histological and immunofluorescence analyses.<h4>Results</h4>Inhibition of TGF-β signaling with SB431542-containing nanoparticles significantly reduced p-Smad2-positive cells in the AVF wall during the early maturation phase (days 7-21) and was associated with decreased AVF wall thickness that showed both decreased collagen density and decreased SMC proliferation. SMC-specific TGF-β signaling disruption decreased collagen density but not SMC proliferation or wall thickness. Endothelial cell-specific TGF-β signaling disruption decreased both collagen density and SMC proliferation in the AVF wall and was associated with reduced wall thickness, increased outward remodeling, and improved AVF patency.<h4>Conclusions</h4>Endothelial cell-targeted TGF-β inhibition may be a translational strategy to improve AVF patency.

<h4>Background</h4>Arterial deterioration is mostly caused by atherosclerosis, which progresses with age. However, we have observed serious backgrounds or etiologies in younger patients with non-atherosclerotic diseases and deterioration of small-to-medium-sized arterial lesions. Therefore, we aimed to identify the specific features of patients aged <40 years with deterioration of small-to-medium-sized arteries.<h4>Methods</h4>We selected patients who were admitted to our department from 1995 to 2019 with deterioration of small-to-medium-sized arteries (aneurysms, dissection, rupture, or arterial injury/damage) and focused on the cohort aged <40 years. We examined the backgrounds or etiologies of the patients including genetic and inflammatory diseases, which might have caused the arterial deterioration.<h4>Results</h4>Consequently, more than half (54.1%) of the patients aged <40 years had non-atherosclerotic comorbid diseases. However, the number of deteriorated arterial lesions was higher in patients aged <40 years than in patients aged ≥40 years (3.13 vs. 1.33 lesion/patient; P = 0.011). Furthermore, the data analysis of patients with multiple arterial lesions (≥3) revealed that the younger population tended to have more specific backgrounds or etiologies, notably Ehlers-Danlos syndrome and Behçet's disease. There were no differences in the all-cause mortality and cardiovascular disease-related mortality between patients aged <40 and ≥40 years (P = 0.89 and 0.29, respectively).<h4>Conclusions</h4>Over 50% of patients aged <40 years with deterioration of small-to-medium-sized arteries had non-atherosclerotic, specific clinical backgrounds or etiologies, including genetic and inflammatory diseases. In addition, they exhibited more arterial lesions than older patients.

We describe a case of sac enlargement that occurred 11 years after emergent open surgical repair of an infected abdominal aortic aneurysm. The diameter of the sac covering the Dacron graft had gradually expanded to 80 mm, and the flow of contrast medium into the sac was suspected. Elective surgery revealed a perigraft seroma and back-bleeding from the remnant wall. After attaining hemostasis, fibrin glue and oxidized cellulose were applied, and sac plication was performed. Thereafter, the sac has not expanded. Open diagnostic treatment should be a good option for cases of postoperative sac enlargement with an unknown origin.

<jats:sec> <jats:title>Objective:</jats:title> <jats:p>Patients with end-stage renal disease depend on hemodialysis for survival. Although arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis, the primary success rate of AVF is only 30% to 50% within 6 months, showing an urgent need for improvement. PD-L1 (programmed death ligand 1) is a ligand that regulates T-cell activity. Since T cells have an important role during AVF maturation, we hypothesized that PD-L1 regulates T cells to control venous remodeling that occurs during AVF maturation.</jats:p> </jats:sec> <jats:sec> <jats:title>Approach and results:</jats:title> <jats:p>In the mouse aortocaval fistula model, anti-PD-L1 antibody (200 mg, 3×/wk intraperitoneal) was given to inhibit PD-L1 activity during AVF maturation. Inhibition of PD-L1 increased T-helper type 1 cells and T-helper type 2 cells but reduced regulatory T cells to increase M1-type macrophages and reduce M2-type macrophages; these changes were associated with reduced vascular wall thickening and reduced AVF patency. Inhibition of PD-L1 also inhibited smooth muscle cell proliferation and increased endothelial dysfunction. The effects of anti-PD-L1 antibody on adaptive venous remodeling were diminished in nude mice; however, they were restored after T-cell transfer into nude mice, indicating the effects of anti-PD-L1 antibody on venous remodeling were dependent on T cells.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Regulation of PD-L1 activity may be a potential therapeutic target for clinical translation to improve AVF maturation.</jats:p> </jats:sec>

<jats:p>Induced pluripotent stem cells (iPSC) represent an innovative, somatic cell-derived, easily obtained and renewable stem cell source without considerable ethical issues. iPSC and their derived cells may have enhanced therapeutic and translational potential compared with other stem cells. We previously showed that human iPSC-derived smooth muscle cells (hiPSC-SMC) promote angiogenesis and wound healing. Accordingly, we hypothesized that hiPSC-SMC may be a novel treatment for human patients with chronic limb-threatening ischemia who have no standard options for therapy. We determined the angiogenic potential of hiPSC-SMC in a murine hindlimb ischemia model. hiPSC-SMC were injected intramuscularly into nude mice after creation of hindlimb ischemia. Functional outcomes and perfusion were measured using standardized scores, laser Doppler imaging, microCT, histology and immunofluorescence. Functional outcomes and blood flow were improved in hiPSC-SMC-treated mice compared with controls (Tarlov score, p &lt; 0.05; Faber score, p &lt; 0.05; flow, p = 0.054). hiPSC-SMC-treated mice showed fewer gastrocnemius fibers (p &lt; 0.0001), increased fiber area (p &lt; 0.0001), and enhanced capillary density (p &lt; 0.01); microCT showed more arterioles (&lt;96 μm). hiPSC-SMC treatment was associated with fewer numbers of macrophages, decreased numbers of M1-type (p &lt; 0.05) and increased numbers of M2-type macrophages (p &lt; 0.0001). Vascular endothelial growth factor (VEGF) expression in ischemic limbs was significantly elevated with hiPSC-SMC treatment (p &lt; 0.05), and inhibition of VEGFR-2 with SU5416 was associated with fewer capillaries in hiPSC-SMC-treated limbs (p &lt; 0.0001). hiPSC-SMC promote VEGF-mediated angiogenesis, leading to improved hindlimb ischemia. Stem cell therapy using iPSC-derived cells may represent a novel and potentially translatable therapy for limb-threatening ischemia.</jats:p>

OBJECTIVE: Arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis, but the primary success rate of AVF remains poor. Successful AVF maturation requires vascular wall thickening and outward remodeling. A key factor determining successful AVF maturation is inflammation that is characterized by accumulation of both T-cells and macrophages. We have previously shown that anti-inflammatory (M2) macrophages are critically important for vascular wall thickening during venous remodeling; therefore, regulation of macrophage accumulation may be an important mechanism promoting AVF maturation. Since CD4+ T-cells such as T-helper type 1 cells, T-helper type 2 cells, and regulatory T-cells can induce macrophage migration, proliferation, and polarization, we hypothesized that CD4+ T-cells regulate macrophage accumulation to promote AVF maturation. Approach and Results: In a mouse aortocaval fistula model, T-cells temporally precede macrophages in the remodeling AVF wall. CsA (cyclosporine A; 5 mg/kg, sq, daily) or vehicle (5% dimethyl sulfoxide) was administered to inhibit T-cell function during venous remodeling. CsA reduced the numbers of T-helper type 1 cells, T-helper type 2, and regulatory T-cells, as well as M1- and M2-macrophage accumulation in the wall of the remodeling fistula; these effects were associated with reduced vascular wall thickening and increased outward remodeling in wild-type mice. However, these effects were eliminated in nude mice, showing that the effects of CsA on macrophage accumulation and adaptive venous remodeling are T-cell-dependent. CONCLUSIONS: T-cells regulate macrophage accumulation in the maturing venous wall to control adaptive remodeling. Regulation of T-cells during AVF maturation may be a strategy that can improve AVF maturation. Graphic Abstract: A graphic abstract is available for this article.

Objective---: Arteriovenous fistulae (AVF) placed for hemodialysis have high flow rates that can stimulate left ventricular (LV) hypertrophy. LV hypertrophy generally portends poor cardiac outcomes, yet clinical studies point to superior cardiac-specific outcomes for patients with AVF when compared to other dialysis modalities. We hypothesize that AVF induce physiologic cardiac hypertrophy with cardioprotective features. Methods---: 9-11 week C57Bl/6 male and female mice were treated with sham laparotomy or an aortocaval fistula via a 25Ga needle. Cardiac chamber size and function were assessed with serial echocardiography, and cardiac CTA. Hearts were harvested at 5 weeks post-operatively, and collagen content assessed with Masson's trichrome. Bulk mRNA sequencing was performed from LV of sham and AVF mice at 10 days. Differentially expressed genes were analyzed using Ingenuity Pathway Analysis (Qiagen) to identify affected pathways and predict downstream biological effects. Results---: Mice with AVF had similar body weight and wet lung mass, but increased cardiac mass compared to sham-operated mice. AVF increased cardiac output while preserving LV systolic and diastolic function, as well as indices of right heart function; all 4 cardiac chambers were enlarged, with slight decrement in relative LV wall thickness. Histology showed preserved collagen density within each of the 4 chambers without areas of fibrosis. RNA sequencing captured 19,384 genes, of which 857 were significantly differentially expressed, including transcripts from extracellular matrix-related genes, ion channels, metabolism, and cardiac fetal genes. Top upstream regulatory molecules predicted include activation of angiogenic (Vegf, Akt1), pro-cardiomyocyte survival (Hgf, Foxm1, Erbb2, Lin9, Areg), and inflammation-related (CSF2, Tgfb1, TNF, Ifng, Ccr2, IL6) genes, as well as the inactivation of cardiomyocyte antiproliferative factors (Cdkn1a, FoxO3, α-catenin). Predicted downstream effects include reduction to heart damage, and increased arrhythmia, angiogenesis, and cardiogenesis. There were no significant sex-dependent differences in the AVF-stimulated cardiac adaptation. Conclusions---: AVF stimulate adaptive cardiac hypertrophy in wild-type mice without heart failure or pathological fibrosis. Transcriptional correlates suggest AVF-induced cardiac remodeling has some cardioprotective, although also arrhythmogenic features.

Aim: To assess the potential of human induced pluripotent stem cell-derived smooth muscle cells (hiPSC-SMC) to accelerate diabetic wound healing. Methods: hiPSC-SMC were embedded in 3D collagen scaffolds and cultured in vitro for 72 h; scaffolds were then applied to diabetic, nude mouse, splinted back wounds to assess in vivo healing. Cultured medium after scaffold incubation was collected and analyzed for expression of pro-angiogenic cytokines. Results: hiPSC-SMC secrete increased concentration of pro-angiogenic cytokines, compared with murine adipose derived stem cells. Delivery of hiPSC-SMC-containing collagen scaffolds accelerates diabetic wound healing and is associated with an increased number of total and M2 type macrophages. Conclusion: hiPSC-SMC promote angiogenesis and accelerate diabetic wound healing, making them a promising new candidate for treatment of diabetic wounds.

OBJECTIVE:The porcine arteriovenous graft model is commonly used to study hemodialysis vascular access failure, with most studies using a bilateral, paired-site approach in either the neck or femoral vessels. In humans, left- and right-sided central veins have different anatomy and diameters, and left-sided central vein catheters have worse outcomes. We assessed the effect of laterality on arteriovenous prosthetic graft patency and hypothesized that left-sided carotid-jugular arteriovenous prosthetic grafts have reduced patency in the porcine model. METHODS:Arteriovenous polytetrafluoroethylene grafts were placed ipsilaterally or bilaterally in 10 Yorkshire male pigs from the common carotid artery to the internal jugular vein. Ultrasound measurements of blood flow velocities and diameters were assessed before graft placement. Animals were sacrificed at 1 week, 2 weeks, or 3 weeks. Patency was determined clinically; grafts and perianastomotic vessels were excised and analyzed with histology and immunostaining. RESULTS:At baseline, left- and right-sided veins and arteries had similar blood flow velocities. Although internal jugular veins had similar diameters at baseline, left-sided carotid arteries had 11% smaller outer diameters (P = .0354). There were 10 left-sided and 8 right-sided polytetrafluoroethylene grafts placed; only 4 of 10 (40%) grafts were patent on the left compared with 7 of 8 (88%) grafts patent on the right (P = .04). Left-sided grafts had increased macrophages at the arterial anastomosis (P = .0007). Left-sided perianastomotic arteries had thicker walls (0.74 vs 0.60 mm; P = .0211) with increased intima-media area (1.14 vs 0.77 mm2; P = .0169) as well as a trend toward 38% smaller luminal diameter (1.6 vs 2.5 mm; P = .0668) and 20% smaller outer diameter (3.0 vs 3.7 mm; P = .0861). Left- and right-sided perianastomotic veins were similar histologically, but left-sided veins had decreased expression of phosphorylated endothelial nitric oxide synthase (P = .0032) and increased numbers of α-actin-positive smooth muscle cells (P = .0022). CONCLUSIONS:Left-sided arteriovenous grafts are associated with reduced short-term patency compared with right-sided grafts in the Yorkshire pig preclinical model of arteriovenous prosthetic grafts. Laterality must be considered in planning and interpreting surgical preclinical models.

Here we describe a hybrid procedure, that is, a combination of open isolation and coil embolization, to treat a saccular middle colic artery aneurysm deep behind the pancreas. The middle colic artery provided the collateral blood flow necessary to bypass a chronic segmental aortic occlusion. For preservation of the collateral vessels, we surgically excluded and bypassed the aneurysm and then performed endovascular embolization of the pancreaticoduodenal arteries flowing into the aneurysm, resulting in complete isolation of the aneurysm without jeopardizing blood flow. This hybrid procedure for visceral artery aneurysms can be effective when the collateral vessels need to be preserved.

Arteriovenous fistulae (AVF) are the most common access created for hemodialysis, but up to 60% do not sustain dialysis within a year, suggesting a need to improve AVF maturation and patency. In a mouse AVF model, Akt1 regulates fistula wall thickness and diameter. We hypothesized that inhibition of the Akt1-mTORC1 axis alters venous remodeling to improve AVF patency. Daily intraperitoneal injections of rapamycin reduced AVF wall thickness with no change in diameter. Rapamycin decreased smooth muscle cell (SMC) and macrophage proliferation; rapamycin also reduced both M1 and M2 type macrophages. AVF in mice treated with rapamycin had reduced Akt1 and mTORC1 but not mTORC2 phosphorylation. Depletion of macrophages with clodronate-containing liposomes was also associated with reduced AVF wall thickness and both M1- and M2-type macrophages; however, AVF patency was reduced. Rapamycin was associated with improved long-term patency, enhanced early AVF remodeling and sustained reduction of SMC proliferation. These results suggest that rapamycin improves AVF patency by reducing early inflammation and wall thickening while attenuating the Akt1-mTORC1 signaling pathway in SMC and macrophages. Macrophages are associated with AVF wall thickening and M2-type macrophages may play a mechanistic role in AVF maturation. Rapamycin is a potential translational strategy to improve AVF patency.

Central venous stenosis is an important entity contributing to arteriovenous fistula (AVF) failure. A murine AVF model was modified to create a partial ligation of the inferior vena cava (IVC) in the outflow of the fistula, mimicking central venous stenosis. Technical aspects of this model are introduced. The aorta and IVC are exposed, following an abdominal incision. The infra-renal aorta and IVC are dissected for proximal clamping, and the distal aorta is exposed for puncture. The IVC at the midpoint between the left renal vein and the aortic bifurcation is carefully dissected to place an 8-0 suture beneath the IVC. After clamping the aorta and IVC, an AVF is created by puncturing the infra-renal aorta through both walls into the IVC with a 25 G needle, followed by ligating a 22 G intra-venous (IV) catheter and IVC together. The catheter is then removed, creating a reproducible venous stenosis without occlusion. The aorta and IVC are unclamped after confirming primary hemostasis. This novel model of central vein stenosis is easy to perform, reproducible, and will facilitate studies on AVF failure.

Objective: Open revascularization of the lower extremity in patients with chronic limb-threatening ischemia (CLTI) does not guarantee limb salvage. Due to the high prevalence of frailty among these patients, we hypothesized that sarcopenia negatively affects limb prognosis. Methods: Seventy-five CLTI patients who underwent open revascularization between 2011 and 2015 were retrospectively reviewed. The lumbar psoas index, which is the ratio of the cross-sectional area of the psoas major muscles to the patients' height squared, was used as a surrogate marker for sarcopenia. Male and female patients were stratified separately according to lumbar psoas index values. The lower two-thirds of the population for each sex were defined as the sarcopenia group, with the higher third defined as the non-sarcopenia group. Results: Comorbidities and ambulatory status did not differ between the sarcopenia (n=50) and non-sarcopenia (n=25) groups. The sarcopenia group had significantly lower overall survival rates than the non-sarcopenia group (60% vs 87% at 3 years, P<0.05). Moreover, the limb salvage rates were significantly lower in the sarcopenia group than in the non-sarcopenia group (73% vs 100% at 2 years, P<0.05). Conclusion: Sarcopenia, as measured by the lumbar psoas index, may predict poor limb prognosis in CLTI patients undergoing open revascularization.

Wound healing is the physiologic response to a disruption in normal skin architecture and requires both spatial and temporal coordination of multiple cell types and cytokines. This complex process is prone to dysregulation secondary to local and systemic factors such as ischemia and diabetes that frequently lead to chronic wounds. Chronic wounds such as diabetic foot ulcers are epidemic with great cost to the healthcare system as they heal poorly and recur frequently, creating an urgent need for new and advanced therapies. Stem cell therapy is emerging as a potential treatment for chronic wounds, and adult-derived stem cells are currently employed in several commercially available products; however, stem cell therapy is limited by the need for invasive harvesting techniques, immunogenicity, and limited cell survival in vivo. Induced pluripotent stem cells (iPSC) are an exciting cell type with enhanced therapeutic and translational potential. iPSC are derived from adult cells by in vitro induction of pluripotency, obviating the ethical dilemmas surrounding the use of embryonic stem cells; they are harvested non-invasively and can be transplanted autologously, reducing immune rejection; and iPSC are the only cell type capable of being differentiated into all of the cell types in healthy skin. This review focuses on the use of iPSC in animal models of wound healing including limb ischemia, as well as their limitations and methods aimed at improving iPSC safety profile in an effort to hasten translation to human studies.

Phlegmasia cerulea dolens (PCD) is caused by obstruction of limb venous return that may result in venous gangrene and limb loss. We present a case of a fistula between a ruptured right common iliac artery aneurysm and the left common iliac vein (ilioiliac arteriovenous fistula [AVF]), which initially manifested as left PCD and acute renal failure. Resection of the aneurysm and repair of the AVF immediately improved the PCD and acute renal failure. We should be aware that an iliac AVF might present as PCD and should keep this in mind.

In atherosclerotic lesions, the endothelial barrier against the bloodstream can become compromised, resulting in the exposure of the extracellular matrix (ECM) and intimal cells beneath. In theory, this allows adequately sized nanocarriers in circulation to infiltrate into the intimal lesion intravascularly. We sought to evaluate this possibility using rat carotid arteries with induced neointima. Cy5-labeled polyethylene glycol-conjugated polyion complex (PIC) micelles and vesicles, with diameters of 40, 100, or 200 nm (PICs-40, PICs-100, and PICs-200, respectively) were intravenously administered to rats after injury to the carotid artery using a balloon catheter. High accumulation and long retention of PICs-40 in the induced neointima was confirmed by in vivo imaging, while the accumulation of PICs-100 and PICs-200 was limited, indicating that the size of nanocarriers is a crucial factor for efficient delivery. Furthermore, epirubicin-incorporated polymeric micelles with a diameter similar to that of PICs-40 showed significant curative effects in rats with induced neointima, in terms of lesion size and cell number. Specific and effective drug delivery to pre-existing neointimal lesions was demonstrated with adequate size control of the nanocarriers. We consider that this nanocarrier-based drug delivery system could be utilized for the treatment of atherosclerosis.

From 2001 to 2012, arterial reconstruction was performed in 306 out of 497 limbs (62%) with critical limb ischemia. The reasons for non-vascularization include high operative risk (36%), extended necrosis or infection (20%), and technical issues (15%). Cumulative patency and limb salvage in collagen disease were significantly worse compared to arteriosclerosis obliterans. Cumulative limb salvage, amputation free survival (AFS), and major adverse limb event and perioperative death (MALE + POD) in patients with end-stage renal disease (ESRD) were significantly worse compared to patients without ESRD, but not significant with regards to graft patency. Our finding suggests that aggressive arterial reconstruction provides satisfactory long-term results in critical limb ischemia so long as case selection for revascularization is properly made. (This article is a translation of J Jpn Coll Angiol 2014; 54: 5–11.)

Aim: The viscoelastic properties of the artery are known to be altered in patients with vascular diseases. However, few studies have evaluated the viscoelasticity of the vascular wall in humans. We sought to investigate the degree of viscoelastic deterioration of the carotid artery and assess its clinical implications.<br>Methods: Between January 2011 and June 2013, patients in whom the toe-brachial index was measured at the vascular laboratory were included in this single-institute retrospective observational study. I^＊, a parameter of viscoelastic deterioration, was computed using a non-invasive ultrasonic Doppler effect sensor on the carotid artery. I^＊ is a non-dimensional value, and I^＊＞0 is considered abnormal. Other patient characteristics were identified and tested for correlations with I^＊.<br>Results: The study included 383 patients. The mean I^＊ value was 0.13±0.22 with a normal distribution. Factors that increased the I^＊ value were a female sex (0.18±0.23 vs. 0.10±0.21, P＜0.001), age ≥ 60 (0.14±0.22 vs. 0.06±0.23, P＜0.05) and systolic blood pressure of ＞140 (0.15±0.22 vs. 0.10±0.22, P＜0.05). I^＊ abnormality was a significant risk factor for coronary artery disease (OR 2.20, 95% CI 1.00-4.80, P＜0.05) in a univariate analysis. In the multivariate analysis, I^＊ abnormality was also found to be an independent risk factor for coronary artery disease (OR 4.56, 95% CI 1.21-30.1, P＜0.05).<br>Conclusions: I^＊ may reflect the degree of atherosclerotic changes in the arterial wall and could possibly be used to predict coronary artery disease.

Objective: In this exploratory study, we used ultrasound speckle-tracking methods, originally used for analyzing cardiac wall motion, to evaluate aortic wall motion.Materials and Methods: We compared 19 abdominal aortic aneurysm (AAA) patients with 10 healthy volunteers (diameter, 48 mm vs. 15 mm). Motion pictures of the axial view of the aneurysm using ultrasonography were analyzed. Circumferential strain and strain rate at 6 equally divided segments of the aorta were semiautomatically calculated. We termed 'peak' strain and strain rate as the maximum of strain and strain rate in a cardiac cycle for each segment. We also evaluated the coefficient of variation of peak strain rate for the six segments.Results: In the aneurysm and control groups, the mean values of peak strain along the 6 segments were 1.5% ± 0.6% vs. 4.7% ± 1.6% (p <0.0001), respectively. The coefficient of variation of the peak strain rate was higher in the AAA group (0.74 ± 0.20) than in the control group (0.56 ± 0.12; p <0.05).Conclusions: Aortic wall compliance decreased in the more atherosclerotic AAA group. The higher relative dispersion of strain rates in the AAA group is indicative of the inhomogeneous movement of the aortic wall.

要 旨：過去12年間に当科に入院した重症虚血肢408例497肢のうち血行再建を施行したものは306肢(62%)で，非血行再建の主な理由としては全身状態不良やハイリスク，広範壊死や感染，技術的不可などであった。血行再建例においては，原疾患として血管炎，また透析の有無が救肢率などの予後に関与していた。重症虚血肢の救肢のためには，適応を十分に考慮したうえで積極的に血行再建をすることが望ましい。

AIM: In Trans-Atlantic Inter-Society Concensus (TASC) II, patients at risk for critical limb ischemia (CLI) without symptoms are termed "chronic subclinical ische mia," but research are still lacking. The objective was to find out whether clinically asymptomatic contralateral limbs at the time of treatment for ipsilateral CLI could be regarded as "chronic subclinical ischemia". METHODS: Ninety-six patients with CLI who had no symptoms in the contralateral limb were retrospectively reviewed. The symptoms of the contralateral limb after initial intervention for the ipsilateral limb were surveyed. Risk factors for developing CLI and tissue loss were then analyzed. RESULTS: Five patients (5.2%) became claudicants, 37 patients (38.5%) had symptoms of CLI, and 14 (14.6%) experienced tissue loss during the follow-up period. The overall CLI-free rates at 12, 36, and 60 months were 79.2%, 55.2%, and 45.8%, respectively, while the tissue loss-free rates at 12, 36, and 60 months were 91.3%, 78.8%, and 78.8%, respectively. Risk factor for developing CLI on the contralateral limb was having skin perfusion pressure (SPP) <40 mmHg at the surgery for ipsilateral limb. The presence of SPP <40 mmHg and end stage renal failure with hemodialysis resulted in a significantly high probability of tissue loss. CONCLUSION: Patients with CLI with an asymptomatic contralateral limb with an SPP value <40 mmHg are at a high risk of developing CLI and tissue loss during the follow-up period. Information on the contralateral limb at initial surgery may help to speculate the fate of the asymptomatic contralateral limb.